Hydrolysis of 3-oximino-delta5(10)steroids

ABSTRACT

3-OXIMINO-$5(10) STEROIDS ARE CONVERTED TO THE CORRESPONDING 3-KETO-$5(10) STEROIDS TREATMENT WITH A TITANIUM (III) OR CHROMIUM (II) SALT.

3,751,438 HYDROLYSIS F S-OXIMINO-M STEROIDS George R. Lenz, Glenview, and Raphael Pappo, Skolne, 111., assignors to G. D. Searle & Co., Chicago, Ill. No Drawing. Filed Jan. 20, 1972, Ser. No. 219,551 Int. Cl. C07c 169/22 U.S. Cl. 269-397.4 14 Claims ABSTRACT OF THE DISCLOSURE 3-oximino-A U0) steroids are converted to the corresponding B-keto-A steroids by treatment with a titaniumlIII) or chromiumfli) salt.

The present invention is concerned with a process for the formation of 3-keto steroids and, in particular, it is concerned with converting 3-oximino-A steroids to 3- keto-A steroids by contacting the 3-oximino compound with a titanium(III) or chromium(II) salt.

It has been surprisingly discovered that when 3-oximino-A steroids of the following partial structural formula RON wherein R is hydrogen or a lower alkanoyl radical are contacted with a titanium salt when R is hydrogen or lower alkanoyl radical, or a chromium salt when R is a lower alkanoyl radical, formation of the 3-keto-A steroid is accomplished without rearrangement of the A500) double bond to the A double bond. The lower alkanoyl radicals represented contain up to 7 carbon atoms and are illustrated by acetyl and propionyl.

Previously, conversion of the oximino moiety had resulted in simultaneous formation of the A double bond. For example, U.S. Pat. 3,507,888 shows that the 3-0):- imino substituent may be converted to the 3-keto substituent with dilute acid such as hydrochloric, sulfuric, acetic, and the like in an organic solvent medium and in all instances the A500) double bond isomerizes to the A double bond.

In the process of this invention, the 3-oximino substituent is converted to the 3-keto substituent by contacting the 3-hydroxyimino-A steroid with a suitable titanium(III) salt or the O-alkanoate with a titaniumflll) or chromium(II) salt while retaining the A configuration. Suitable titanium salts are illustrated by titanium trichloride, titanium tribromide, titanium trifluoride, titanium triacetate and titaniumflll) sulfate, with titanium trichloride being particularly preferred. Suitable chromium salts are illustrated by chromous acetate, chromous chloride and chromous sulfate, with chromous acetate being particularly preferred.

The starting materials used in the practice of this invention can be prepared from available 3-keto-A steroids by their reaction with hydroxylamine or suitable salts of hydroxylamine. For example, by the methods described in U.S. Pat. 3,507,888, 3,17-diketo-A estrenes are converted to 3-oximino-l7-keto-A estrenes. Typically, an ethanolic solution of a 3,17-diketone is contacted with hydroxylamine hydrochloride and pyridine to yield the 3-hydroxyimino-17-keto derivative. The oximino substit- United States Patent 0 Patented Aug. 7, 1973 cut functions as a protective group and thus substitutions can be made at the l7-positi on in those compounds by usual methods Without affecting the 3-oximino moiety. The O-alkanoates are formed by treating the 3-hydroxymime-A steroids with the appropriate acid anhydride. For example, treatment of 3-hydroxyiminoestr-5(l0)-en- 17 8-01 with acetic anhydride afiords S-acetoxyiminoestr- 5(10)-en-17fi-ol. The 3-keto-A group then is regenerated by the process of the present invention.

The choice of solvent is acritical, with dioxane, tetrahydrofuran, acetic acid, dimethylformamide, acetone and their aqueous solutions being illustrative. Dioxane, however, is particularly preferred when the titanium salt is employed and tetrahydrofuran is preferred when the chromium salt is used. Solution aids, such as acetic acid, and bufiers, such as ammonium acetate, can be added to the reaction mixture if desired. The process generally is carricd out under an inert atmosphere such as nitrogen and in a temperature range of about 10-65 C. but is not limited thereto.

The instant process is rapid, results in few undesired products and gives high yields, with the desired product being easily isolable from the reactants. Simple extraction procedures may be used to recover the product of the process. Typically, chloroform-water or methylene chloride-water provides an excellent system for the extraction procedure.

In a preferred embodiment of the instant process 3-oximino A steroids of the following structural formula R ON with R being hydrogen or a lower alkanoyl radical and R being hydrogen or a lower alkyl, lower alkenyl or lower alkynyl radical are contacted with titanium trichloride when R is hydrogen or a lower alkanoyl radical or chromous acetate when R is a lower alkanoyl radical to produce the corresponding S-keto-A steroids. The lower alkyl radicals represented contain up to 7 carbon atoms and are illustrated by methyl, ethyl, propyl, and isopropyl, the lower alkenyl radicals contain up to 7 carbon atoms and are illustrated by vinyl, allyl and propenyl, the lower alkynyl radicals contain up to 7 carbon atoms and are illustrated by ethynyl and propynyl and the lower alkanoyl radicals are the same as described hereinbefore.

The products produced by the process of the present invention are useful as pharmacological agents. For example, 17oz ethynyl 17,8 hydroxyestr-5( lO)-en-3-one, produced from 17a-ethynyl-3-hydroxyiminoestr-5(10)- en-17fi-ol by the instant process, has potent hormonal activity as described in U.S. Pat. 2,725,389. That compound is used commercially in progestational preparations. The hormonal activity of the lt-(1OWBI' alkyl)- 3 17,3-hydroxyestr-5(10)-en-3-one is described in U.S. Pat. 2,905,676.

The invention will appear more fully from the ex amples which follow. They are given by way of illustration only and are not intended to limit the invention either in spirit or in scope as many modifications in materials and methods will be apparent to those skilled in the art. In the following examples, temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight unless specified otherwise.

EXAMPLE 1 1.00 part of 3-hydroxyiminoestr-5 (10)-en-17/3-ol is dissolved in 10.34 parts of dioxane. Then 5.0 parts of ammonium acetate and 2 parts by volume of a 50% aqueous acetic acid solution are added successively to that solution. The reaction mixture is stirred under nitrogen and 12.5 parts by volume of an aqueous 20% titanium trichloride solution is added. After stirring for 1 hour, the mixture is poured into water and extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate, and evaporated to dryness. The material which remains is recrystallized from etherpetroleum ether to give 17,8-hydroxyestr-S(10) -en-3-one, melting at about 179-l8l.

EXAMPLE 2 When an equivalent quantity of 17a-ethyny1-3-hydroxyiminoestr-5 (10)-en-1718-ol is substituted in the procedure of Example 1, there is produced l7a-ethynyl-l7fi-hydroxyestr-5 10) -en-3-one.

EXAMPLE 3 By substituting an equivalent quantity of 17a-methyl- 3-hydroxyiminoestr-5 (10)-en-1718-ol in the procedure of Example 1, there is afforded 17 a-methy1-17p-hydroxyestr- 5( l)-en3-one.

EXAMPLE 4 A mixture of 0.5 part of 3-hydroxyiminoestr-5(10)- en-l7fl-ol, 2.16 parts of acetic anhydride and 6.7 parts of methylene chloride is allowed to stand for /2 hour. Then the total solution volume is brought up to 50 parts by volume by the addition of methanol, and several parts of water is added. After 2 hours the solution is added in one portion to methylene chloride and the combined solution is extracted with dilute sodium carbonate. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed by evaporation. The 3-acetoxyiminoestr-5(10)-en-17fl-ol product, which remains as an oil, is dissolved in 19.5 parts of tetrahydrofuran containing 2 parts of water. Then 2 parts of chromous acetate is added and the solution is stirred under nitrogen at 65 for three hours. After that time, 267 parts of methylene chloride is added and the solution is passed through a column containing sodium sulfate, then treated with charcoal and again filtered through a column of sodium sulfate. The filtrate is evaporated under reduced pressure and the oil remaining is recrystallized from ether-petroleum ether to yield 17fl-hydroxyestr-5(l0) en-3-one. That compound is identical to the compound obtained in Example 1.

EXAMPLE 5 By substituting an equivalent quantity of l7a-ethynyl- 3-hydroxyiminoestr-5 ()-en-17 8-01 in the procedure of Example 4, there is produced l7a-ethynyl-l7 3-hydroxyestr-5 (10)-en-3-one. That product is identical to the product of Example 2.

EXAMPLE 6 When an equivalent quantity of 17a-methyl-3-hydroxyiminoestr-5(10)-en-17/8-ol is substituted in the procedure of Example 4, there is afforded 17a-methyl-17 3-hydroxyestr-5(10)-en-3-one. That product is identical to the product obtained in Example 3.

4 EXAMPLE 7 Substitution of an equivalent quantity of propionic anhydride in the procedure of Example 4 and otherwise following the procedure of Example 4 affords 17,6-hydroxyestr-5(10)-en-3-one, identical to the product of Example 4.

EXAMPLE 8 By substituting equivalent quantities of 17u-(1-propynyl)-3-hydroxyiminoestr-5 10) -en-17B-ol, 17a vinyl- 3-hydroxyiminoestr-5(10)-en-17fl-ol, 17oz propenyl-3 -hydroxyiminoestr-S 10) -en-17;8-ol and 17m-ethyl-3-hydroxyiminoestr-5(l0)-en-17B-ol in the procedure of Example 1, there is afforded, respectively, 1713-hydroxy-l7a-( l-propynyl)estr-5(10)-en-3-one, 17 9-hydroxy 17o: vinylestr- 5(10)-en-3-one, l7/3-hydroxy 17a propenylestr-S (10)- en-3-one and 1700 ethyl-17fi-hydroxyestr-5(10)-en-3-one.

EXAMPLE 9 Substitution of equivalent quantities of 17a-(1-propynyl)-2-hydroxyiminoestr-5(10) en -01, 17a-vinyl- 3-hydroxyiminoestr-5(10)-en-17 3-ol, 17a propenyl-3-hydroxyiminoestr-S(10)-en-17fl-ol and 17u-ethyl-3-hydroxyiminoestr-5(10)-en-175-ol in the procedure of Example 4, yields, respectively, 17,8 hydroxy-17a-(l-propynyl)estr- 5 (10)-en-3-one, 17,3-hydroxy 171x. vinylestr-5(10)-en- 3-one, 17fi-hydroxy-l7u-propenylestr-5(10) en 3-one and 17a-ethyl-17/3-hydroxyestr-5(10)-en-3-one. The products are identical to the products described in Example 8.

What is claimed is:

1. The process which comprises contacting a A -3- oximino steroid of the structural formula RON wherein R is hydrogen or a lower alkanoyl radical and R' is hydrogen or a lower alkyl, lower alkenyl or lower alkynyl radical with a metallic salt selected from the group consisting of chromium(II) and titanium(III) salts, with the provision that when R is lower alkanoyl, the metallic salt is a chromium(II) salt and when R is hydrogen or lower alkanoyl, the metallic salt is titanium(III) salt, and isolating the resulting A -3-keto steroid.

2. The process of claim 1 which comprises contacting a A -3-oximino steroid of the structural formula of claim 1 wherein R is hydroegn with a titaniumflll) salt and isolating the resulting A -3-keto steroid.

3. The process of claim 2, wherein the titanium salt is selected from the group consisting of titanium trichloride, titanium tribromide, and titanium trifiuoride.

4. The process of claim 2, wherein the titanium salt is titanium trichloride.

5. The process of claim 4, wherein the A -3-oximino steroid is 3-hydroxyiminoestr-5 10 -en- 175-01.

6. The process of claim 4, wherein the A -3-oximino steroid is 17a-ethynyl-3-hydroxyiminoestr-5 (10)-en-17pol.

7. The process of claim 1 which comprises contacting a A -3-oximino steroid of the structural formula of claim 1 wherein R is a lower alkanoyl radical with a chromium(II) salt and isolating the resulting A -3- keto steroid.

8. The process of claim 7, wherein the chromium salt is selected from the group consisting of chromous acetate, chromous chloride and chromous sulfate.

9. The process of claim 7, wherein the chromium salt is chromous acetate.

10. The process of claim 9, wherein the A -3-oximino steroid is 3-acetoxyiminoestr-5(10)-en-17 3-ol.

5 6 11. The process of claim 9, wherein the A -3-ox- 13. As in claim 12, the compound which is 17a-ethyirnino steroid is 17a-ethynyl-3-acetoxyimino-5(10)-ennyl-3-acetoxyiminoestr-5(10)-en-17B-ol. 1713-01. 14. As in claim 12, the compound which is 3-acetoxy- 12. A compound of the formula iminoestr-S (10)-en-17;3-ol.

References Cited UNITED STATES PATENTS 3,060,205 10/1962 Schwenk et a1 260397.5 10 3,282,915 11/1966 Jiu et a1. 260192 3,507,888 4/1970 Klimstra 260-3973 RON HENRY A. FRENCH, Primary Examiner wherein R is a lower alkanoyl radical and R is selected U.S. C1. X.R.

from the group consisting of hydrogen, lower alkyl, lower 15 260-397.5, 999 alkenyl and lower aikynyl radical. 

